Objectives 1) Explain what's meant by dominant and recessive phenotypes and alleles!2) Be able to identify classic mendelian types of hereditary:!- autosomal dominant, autosomal recessive, X-linked dominant, and X-linked recessive!3) Explain how factors such as reduced penetrance, delayed age of onset, variable expressivity, and pleiotropy affect the phenotypic expression of a disease and the observed pattern of inheritance!!! 1) Explain what's meant by dominant and recessive phenotypes and alleles - mutation= a change in DNA seqence-->change in protein expression!- allele= different forms of the same gene Ex. WT, mutant, null!- phenotype= the physical appearance (incl. symptoms) of a trait!- genotype= the allele associated with a trait!- Transition mutation= stays in same class. Ex. pur-> pur (CUT= pyrimidine, AG= purine)!- Transversion mutation= changes class!- Nucleotide change favors certain spots (mutation hotspot!)!- null allele (loss of function)= no gene product!- hypomorph= decreased amt/activity!- gain of function= increased amt/activity - dominant negative= antagonizes normal product - neomorph= novel activity of a protein!- All but silent or conservative missense sequence changes are likely to significantly alter product function - polymorphism= a change in DNA seq. that isn't disease causing, usually in >1% of the population 2) Be able to identify classic mendelian types of hereditary: - autosomal dominant - males and females equally affected - only one abnormal allele to have the phenotype!- 1/2 chance of affected offspring from affected parent!- male-->male transmission!- structural genes, transcription factors!- Ex. Neurofibromatosis, the most common autosomal dom. condition. Mut. NF1 gene, large gene!- Fully penetrant= everyone who had a mut. in the gene will get the condition!- Expression can be variable= individs with the same mutation can have diff. disease severity!- Co-dominant expression: alleles that are both expressed when they occur in the heterozygous state!- Ex. ABO blood group antigens!- Variations: new mutations!- more easily seen in a large gene, paternal age effects!- 10^-4 to 10^-7 per locus/cell division!- Ex. Achondroplasis!- Autosomal dom.!- 100% penetrance!- 80% new mutations (de novo event)!- mutation in FGFR3!- slows bone growth!- gain of function mutation!!!!!- Autosomal Recessive - males and females equally affected!- seen in sibs, but not really other relatives!- risk of recurrence in sibs 25%!- 2/3 of unaffected sibs are carriers, consanguinity (inbreeding) increases risk of sharing a common ancestral mutation !!!- transcription from one allele is sufficient!- what we say is homozygosity is usually compound heterozygosity at molecular levels. Aka both knocked out function of that gene, just at diff places/diff ways. Can knock it out to diff. degrees. Allelic heterogeneity is common. - Loss of function alleles= likely when pt. muts give the same phenotype as deletion of the allele!- inherited as recessive traits when 50% of expression is sufficient for normal phenotype!- Phenotypes can vary based on the nature of the mutation!- Ex. oculocutaneous albinism, autosom. rec. mut. Can get a mutation that leads to no enzyme activity or to residual enzyme activity. Also, other genes in the pathway of pigment production can give albinism--there are 4 autosom. genes involved in separate albinism conditions!- aka you can ding other parts of the pathway and get a similar phenotype!- Lyonization= X inactivation (to deal with gene dosage diffs between XY and XX). !- 1 X is active in each cell and 1 X is inactive in each cell!- As a result, female are mosaic for their X-linked gene manifestations!- all are functionally hemizygous!- skewed lyonization= shifting from random distribution may result in manifestation of disease in females - X-linked recessive - affects mainly males, affected males normally born to unaffected parents!- females can be affected if born to an affected father and a carrier mom OR if they have very skewed lyonization!- NO male to male transmission!- males born to carrier mom have a 50% risk of inheriting altered gene!!!!!!!!!!Ex. Duchenne muscular dystrophy!- dystropin gene has a high mut. rate! - X-linked dominant!- males and females are both affected, but typically males are worse than females!- if male female, only affected females are observed!- affected males will only have affected daughters and unaffected sons (NO MALE TO MALE TRANSMISSION)!Ex. Incontinentia pigmenti! 3) Explain how factors such as reduced penetrance, delayed age of onset, variable expressivity, and pleiotropy affect the phenotypic expression of a disease and the observed pattern of inheritance - Pleiotropy= when one gene influences multiple, seemingly unrelated phenotypic traits!- Ex. Marfan syndrome (heart-dilation of aortic arch, eyes-dislocated lenses, skeletal-long bone growth)!- Variable expressivity= everybody with the disease does have symptoms, just have different symptoms!- Reduced penetrance= have a mutation--> but you may not have the disease aka carry the allele, but never manifest the phenotypic evidence of this. Is an all or nothing phenomenon in expression of a train ina population.!- Ex. Familial Retinoblastoma: autosom. dom. in the person, recessive in the cell. A second mutation is req. in the Rb gene to have the Rb phenotype. If the individ. never has the second mutation, then they don't manifest retinoblastoma.!!- Sex-limited (autosomal dom. trait)= only one of the sexes (male or female) shows the trait!ex. Familial precocious puberty--due to gain of func. mutation !!!!!!!!!!!!!!!- Variation in age of onset (autosom. dom.) - Ex. Huntinton's Chorea, triplet repeat expansion that can expand, age of onset usually after
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